EP1292609A2 - Peptide, zusammesetzungen und verfahren zur behandlung von burkholderia cepacia - Google Patents

Peptide, zusammesetzungen und verfahren zur behandlung von burkholderia cepacia

Info

Publication number
EP1292609A2
EP1292609A2 EP01948413A EP01948413A EP1292609A2 EP 1292609 A2 EP1292609 A2 EP 1292609A2 EP 01948413 A EP01948413 A EP 01948413A EP 01948413 A EP01948413 A EP 01948413A EP 1292609 A2 EP1292609 A2 EP 1292609A2
Authority
EP
European Patent Office
Prior art keywords
alkyl
terminus
tryptophan
amino acids
optionally substituted
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP01948413A
Other languages
English (en)
French (fr)
Inventor
Carla H. Kuhner
James A. Romesser
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Hercules LLC
Original Assignee
Hercules LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Hercules LLC filed Critical Hercules LLC
Publication of EP1292609A2 publication Critical patent/EP1292609A2/de
Withdrawn legal-status Critical Current

Links

Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K7/00Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04Linear peptides containing only normal peptide links
    • C07K7/06Linear peptides containing only normal peptide links having 5 to 11 amino acids
    • AHUMAN NECESSITIES
    • A01AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01NPRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N47/00Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid
    • A01N47/40Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having a double or triple bond to nitrogen, e.g. cyanates, cyanamides
    • A01N47/46Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having a double or triple bond to nitrogen, e.g. cyanates, cyanamides containing —N=C=S groups
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00Drugs for disorders of the respiratory system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04Antibacterial agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04Antibacterial agents
    • A61P31/06Antibacterial agents for tuberculosis
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04Antibacterial agents
    • A61P31/08Antibacterial agents for leprosy
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10Antimycotics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12Antivirals
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12Antivirals
    • A61P31/14Antivirals for RNA viruses
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12Antivirals
    • A61P31/14Antivirals for RNA viruses
    • A61P31/16Antivirals for RNA viruses for influenza or rhinoviruses
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12Antivirals
    • A61P31/14Antivirals for RNA viruses
    • A61P31/18Antivirals for RNA viruses for HIV
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12Antivirals
    • A61P31/20Antivirals for DNA viruses
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00Antiparasitic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00Antiparasitic agents
    • A61P33/02Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A61P33/04Amoebicides
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00Antiparasitic agents
    • A61P33/02Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A61P33/06Antimalarials
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00Antiparasitic agents
    • A61P33/10Anthelmintics
    • A61P33/12Schistosomicides
    • CCHEMISTRY; METALLURGY
    • C02TREATMENT OF WATER, WASTE WATER, SEWAGE, OR SLUDGE
    • C02FTREATMENT OF WATER, WASTE WATER, SEWAGE, OR SLUDGE
    • C02F1/00Treatment of water, waste water, or sewage
    • C02F1/50Treatment of water, waste water, or sewage by addition or application of a germicide or by oligodynamic treatment
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K14/00Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/001Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof by chemical synthesis
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00Medicinal preparations containing peptides
    • CCHEMISTRY; METALLURGY
    • C02TREATMENT OF WATER, WASTE WATER, SEWAGE, OR SLUDGE
    • C02FTREATMENT OF WATER, WASTE WATER, SEWAGE, OR SLUDGE
    • C02F2303/00Specific treatment goals
    • C02F2303/20Prevention of biofouling
    • CCHEMISTRY; METALLURGY
    • C02TREATMENT OF WATER, WASTE WATER, SEWAGE, OR SLUDGE
    • C02FTREATMENT OF WATER, WASTE WATER, SEWAGE, OR SLUDGE
    • C02F2305/00Use of specific compounds during water treatment
    • C02F2305/14Additives which dissolves or releases substances when predefined environmental conditions are reached, e.g. pH or temperature
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02ATECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • This invention relates to peptides possessing antimicrobial activity and methods of using them to combat microbes.
  • Peptides of the present invention are particularly useful in the treatment of Burkholderia cepacia in industrial and clinical environments.
  • Peptides are now recognized as part of a global defense mechanism used by animals and plants in terrestrial and marine environments to prevent microbial attack.
  • the discovery of antimicrobial peptides has generated interest in the use of these compounds to combat clinically relevant microorganisms, in particular, multi-drug resistant organisms.
  • Large screening programs have been developed to identify potential peptide-based drug candidates from both natural product-and combinatorial chemistry-derived libraries.
  • Antimicrobial peptides are also potential candidates for the prevention of biofouling in industrial water systems, where they would represent a novel chemical class of antibiofouling compounds.
  • Peptides are produced naturally in bacteria, fungi, plants, insects, amphibians, crustaceans, fish and mammals [Hancock, Advances in Microbial Physiology, 135-175, Academic Press (1995)]. They represent a major inducible defense against microbes and their production in the immune system of many species is controlled by transcriptional elements. For instance, in humans, antimicrobial peptides are found in neutrophils which are responsible for responding against invasion of foreign organisms [Lehrer et al. ASM News, 56, 315-318, (1990)]. Natural antimicrobial peptides have a moderate spectrum of activity against microbes and are usually present in moderate amounts.
  • Natural antimicrobial peptides of 12-50 amino acid residues have been obtained in the past 20 years via isolation from the defense systems of insects, amphibians and mammals [Oh et al. J. Peptide Res., 56, 41-46, (1998)]. Use of these peptides in clinical trials has shown effective antimicrobial activity [Hancock, Exp. Opin. Invest. Drugs, 7, 167-174, (1998)].
  • the charge distribution and hydrophobic properties of a peptide appear to be important factors in determining its effectiveness.
  • the peptides are usually large (12-50 amino acids) and said to be cationic due to the presence of positively charged basic amino acid residues such as arginine and lysine [Hancock, Exp. Opin. Invest. Drugs, 7, 167-174, (1998)]. It is suggested that the cationicity of the peptide may play an important role in the peptide interaction with negatively charged membranes. For instance, cationic peptides are said to compete with divalent cations on the surface of Gram-negative bacteria and prevent their interaction with lipopolysacchari.de (LPS) molecules [Hancock, Exp. Opin. Invest. Drugs, 7, 167-174, (1998)]. It is hypothesized that the displacement of divalent cations by cationic peptides creates a distortion in the outer membrane of the bacteria through which peptides may pass.
  • LPS lipopolysacc
  • Industrial facilities employ many methods of preventing bio fouling of industrial water systems. Many microbial organisms are involved in biofilm formation in industrial waters. Growth of slime-producing bacteria in industrial water systems causes problems including decreased heat transfer, fouling and blockage of lines and valves, and corrosion or degradation of surfaces. Control of bacterial growth in the past has been accomplished with biocides. Many biocides and biocide formulations are known in the art. However, many of these contain components which may be environmentally deleterious or toxic, and are often resistant to breakdown.
  • the manufacturing cost of peptides may be a limiting factor in their antimicrobial application [Hancock and Lehrer, TiB Tech., 16, 82-88, (1998)].
  • the long chain length of the natural antimicrobial peptides is a major factor contributing to their cost of synthesis.
  • U.S. Pat. No. 5,504,190 describes a process for solid-support synthesis of equimolar oligomer mixtures that prevents unequal reaction yields during addition of blocked amino acids and allows for equal and precise representation of amino acid residues along the chain of the peptide.
  • the peptides synthesized are said to exhibit antimicrobial activity, and contain equimolar amounts of preferably at least 6 amino acid residues.
  • the peptides disclosed include 6-mer oligopeptide mixtures beginning with Ac-Arg-Arg-, Ac-Trp-Trp-, Ac-Cys-Cys-, Ac-Trp-Cys-, Ac-Trp-Leu-, Ac-Trp-Lys-, Ac-Arg-Trp-, Ac-Thr-Arg-, Ac-Gln-Tyr-, and Ac- Arg-Met-.
  • U.S. Pat. No. 5,786,324 discloses peptides that are minimally 10 amino acids long and are lysine and arginine rich. These peptides showed antimicrobial activity against Gram- negative bacteria including Pseudomonas aeruginosa but were not active against Burkholderia cepacia.
  • U.S. Pat. No. 5,736,533 discloses an oligosaccharide compound which is said to be effective against bacteria consisting of Streptococcus pneumoniae, Haemophilus influenza, Haemophilus parainfluenza, and Burkholderia cepacia.
  • Burkholderia is also a nosocomial pathogen and causes infections due to contaminated equipment, medications and disinfectants. Infections include bacteremia due to contamination of indwelling catheters, urinary tract infection, peritonitis and respiratory tract infection.
  • B. cepacia is an important pathogen in cystic fibrosis and chronic granulomatous disease. In cystic fibrosis patients, B. cepacia is the major organism responsible for morbidity and mortality. B. cepacia is one of the most antibiotic resistant organisms isolated in the clinical laboratory. The present invention provides safe and effective peptides with activity against Burkholderia cepacia for use in clinical and industrial settings.
  • the invention provides antimicrobial compositions comprising a plurality of peptides, wherein said peptides each are represented by Formula I:
  • R ⁇ is C,-C 20 alkyl; C 3 -C 6 cycloalkyl; C 4 -C 20 alkenyl; C 4 -C 20 alkynyl; -C 20 haloalkyl; C 3 -C 20 haloalkenyl; C 3 -C 20 haloalkynyl; C 2 -C 20 alkoxyalkyl; C 2 -C 20 alkylthioalkyl; C 2 -C 20 alkylsulfinylalkyl; C 2 -C 20 alkylsulfonylalkyl; C 5 -C 20 cycloalkylalkyl; C 4 -C 20 alkenyloxyalkyl; C 4 -C 20 alkynyloxyalkyl; C 4 -C 20 (cycloalkyl) oxyalkyl; C 4 -C 20 alkenylthioalkyl; C 4 -C 20 alkynylthioalkyl; C
  • R 3 is independently hydrogen; C r C 4 alkyl; or phenyl optionally substituted with at least one R 8 ;
  • R 4 is independently hydrogen; -Cg alkyl; or phenyl optionally substituted with at least one R 8 ;
  • R 5 is independently C r C 6 alkyl; C r C 6 alkoxy; C r C 6 haloalkyl; halogen; C 2 -C 8 alkynyl; - thioalkyl; phenyl or phenoxy each optionally substituted with at least one R 8 ; cyano; nitro; C r C 6 haloalkoxy; - haloalkythio; C 2 -C 6 alkenyl; C 2 -C 6 haloalkenyl; acetyl; CO 2 CH 3 ; or N(C r C 2 alkyl) 2 ;
  • R 6 is independently methyl; ethyl; methoxy; methylthio; halogen; or trifluoromethyl;
  • R 7 is independently halogen
  • R 8 is independently halogen; C r C 4 alkyl; C r C 4 alkoxy; C r C 4 haloalkyl; nitro; or cyano; wherein: the amino acid in the first position, based on numbered amino acids from N-terminus to C-terminus, is selected from the group consisting of arginine, lysine, methionine, serine, threonine and tryptophan; the amino acid in the second position, based on numbered amino acids from N- terminus to C-terminus, is selected from the group consisting of arginine, histidine, cysteine, threonine, tyrosine, and tryptophan; and the amino acids in positions three through six, based on numbered amino acids from N- terminus to C-terminus, are any amino acid; wherein the first two amino acids of said hexapeptides are other than arginine arginine, tryptophan-tryptophan, tryptophan-c
  • the invention also provides antimicrobial compositions comprising a plurality of peptides, wherein said peptides each are represented by Formula II:
  • R- is C--C 20 alkyl; C 3 -C 6 cycloalkyl; C 4 -C 20 alkenyl; C 4 -C 20 alkynyl; C C 20 haloalkyl; C 3 -C 20 haloalkenyl; C 3 -C 20 haloalkynyl; C 2 -C 20 alkoxyalkyl; C 2 -C 20 alkylthioalkyl; C 2 -C 20 alkylsulfinylalkyl; C 2 -C 20 alkylsulfonylalkyl; C 5 -C 20 cycloalkylalkyl; C 4 -C 20 alkenyloxyalkyl; C 4 -C 20 alkynyloxyalkyl; C 4 -C 20 (cycloalkyl) oxyalkyl; C 4 -C 20 alkenylthioalkyl; C 4 -C 20 alkynylthioalkyl; C 6
  • R 2 is C r C 2 ⁇ alkyl; C 3 -C 6 cycloalkyl; C 4 -C 20 alkenyl; C 4 -C 20 alkynyl; C r C 20 haloalkyl; C 3 -C 20 haloalkenyl; C 3 -C 20 haloalkynyl; C 2 -C 20 alkoxyalkyl; C 2 -C 20 alkylthioalkyl; C 2 -C 20 alkylsulfinylalkyl; C 2 -C 20 alkylsulfonylalkyl; C 5 -C 20 cycloalkylalkyl; C 4 -C 20 alkenyloxyalkyl; C 4 -C 20 alkynyloxyalkyl; C 4 -C 20 (cycloalkyl) oxyalkyl; C 4 -C 20 alkenylthioalkyl; C 4 -C 20 alkynylthioalkyl
  • R 3 is independently hydrogen; - alkyl; or phenyl optionally substituted with at least one R 8 ;
  • R 4 is independently hydrogen; - alkyl; or phenyl optionally substituted with at least one R s ;
  • R 5 is independently C r C 6 alkyl; C r C 6 alkoxy; C ] -C 6 haloalkyl; halogen; C 2 -C 8 alkynyl; C r C 6 thioalkyl; phenyl or phenoxy each optionally substituted with at least one R 8 ; cyano; nitro; - haloalkoxy; C ⁇ -C 6 haloalkythio; C 2 -C 6 alkenyl; C 2 -C 6 haloalkenyl; acetyl; CO 2 CH 3 ; orN(C r C 2 alkyl) 2 ;
  • R 6 is independently methyl; ethyl; methoxy; methylthio; halogen; or trifluoromethyl;
  • R 7 is independently halogen
  • R 8 is independently halogen; C r C 4 alkyl; -Q alkoxy; C 5 -C 4 haloalkyl; nitro; or cyano; wherein: the amino acid in the first position, based on numbered amino acids from N-terminus to C-terminus, is selected from the group consisting of arginine, lysine, methionine, serine, threonine and tryptophan; the amino acid in the second position, based on numbered amino acids from N- terminus to C-terminus, is selected from the group consisting of arginine, histidine, cysteine, threonine, tyrosine, and tryptophan; and the amino acids in positions three through six, based on numbered amino acids from N- terminus to C-terminus, are any amino acid.
  • the invention provides antimicrobial compositions comprising a plurality of hexapeptides, wherein for each hexapeptide, the amino acid in the first position, based on numbered amino acids from N-terminus to C-terminus, is selected from the group consisting of arginine, lysine, methionine, serine, threonine and tryptophan; the amino acid in the second position, based on numbered amino acids from N-terminus to C-terminus, is selected from the group consisting of arginine, histidine, cysteine, threonine, tyrosine, and tryptophan; the amino acids in positions three through six, based on numbered amino acids from N-terminus to C-terminus, are any amino acid; and wherein the first two amino acids of said hexapeptides are other than arginine-arginine, tryptophan-tryptophan, tryptophan- cysteine, tryptophan-lysine
  • the invention provides antimicrobial compositions comprising a plurality of peptides, wherein said peptides each are represented by Formula I: o
  • Ri is C J -C JO alkyl; C 3 -C 6 cycloalkyl; C 4 -C 20 alkenyl; C 4 -C 20 alkynyl; C j -C 20 haloalkyl; C 3 - C 20 haloalkenyl; C 3 -C 20 haloalkynyl; C 2 -C 20 alkoxyalkyl; C 2 -C 20 alkylthioalkyl; C 2 -C 20 alkylsulfinylalkyl; C 2 -C 20 alkylsulfonylalkyl; C 5 -C 20 cycloalkylalkyl; C 4 -C 20 alkenyloxyalkyl; C 4 -C 20 alkynyloxyalkyl; C 4 -C 20 (cycloalkyl) oxyalkyl; C 4 -C 20 alkenylthioalkyl; C 4 -C 20 alkynylthioal
  • R 3 is independently hydrogen; C r C 4 alkyl; or phenyl optionally substituted with at least one R 8 ;
  • R 4 is independently hydrogen; C C 8 alkyl; or phenyl optionally substituted with at least one R 8 ;
  • R 5 is independently C r C 6 alkyl; C r C 6 alkoxy; C r C 6 haloalkyl; halogen; C 2 -C 8 alkynyl; C ⁇ -C 6 thioalkyl; phenyl or phenoxy each optionally substituted with at least one R 8 ; cyano; nitro; C r C 6 haloalkoxy; C ⁇ -C 6 haloalkythio; C 2 -C 6 alkenyl; C 2 -C 6 haloalkenyl; acetyl; CO 2 CH 3 ; orN(C r C 2 alkyl) 2 ;
  • R 6 is independently methyl; ethyl; methoxy; methylthio; halogen; or trifluoromethyl;
  • R 7 is independently halogen; and R 8 is independently halogen; C,-C 4 alkyl; C r C 4 alkoxy; C C 4 haloalkyl; nitro; or cyano; wherein: the amino acid in the first position, based on numbered amino acids from N-teraiinus to C- terminus, is selected from the group consisting of arginine, lysine, methionine, serine, threonine and tryptophan; the amino acid in the second position, based on numbered amino acids from N-terminus to C-terminus, is selected from the group consisting of arginine, histidine, cysteine, threonine, tyrosine, and tryptophan; the amino acids in positions three through six, based on numbered amino acids from N- terminus to C-terminus, are any amino acid; and wherein the first two amino acids of said hexapeptides are other than arginine-arginine, tryptophan-try
  • the invention provides antimicrobial compositions comprising a plurality of peptides, wherein said peptides each are represented by Formula II:
  • Rj is C r C 20 alkyl; C 3 -C 6 cycloalkyl; C 4 -C 20 alkenyl; C 4 -C 20 alkynyl; - o haloalkyl; C 3 - C 20 haloalkenyl; C 3 -C 20 haloalkynyl; C 2 -C 20 alkoxyalkyl; C 2 -C 20 alkylthioalkyl; C 2 -C 20 alkylsulfinylalkyl; C 2 -C 20 alkylsulfonylalkyl; C 5 -C 20 cycloalkylalkyl; C 4 -C 20 alkenyloxyalkyl; C 4 -C 20 alkynyloxyalkyl; C 4 -C 20 (cycloalkyl) oxyalkyl; C 4 -C 20 alkenylthioalkyl; C 4 -C 20 alkynylthioalkyl; C
  • R 2 is C,-C 20 alkyl; C 3 -C 6 cycloalkyl; C 4 -C 20 alkenyl; C 4 -C 20 alkynyl; C r C 20 haloalkyl; C 3 - C 20 haloalkenyl; C 3 -C 20 haloalkynyl; C 2 -C 20 alkoxyalkyl; C 2 -C 20 alkylthioalkyl; C 2 -C 20 alkylsulfinylalkyl; C 2 -C 20 alkylsulfonylalkyl; C 5 -C 20 cycloalkylalkyl; C 4 -C 20 alkenyloxyalkyl; C 4 -C 20 alkynyloxyalkyl; C 4 -C 20 (cycloalkyl) oxyalkyl; C 4 -C 20 alkenylthioalkyl; C 4 -C 20 alkynylthioalkyl;
  • R 3 is independently hydrogen; - alkyl; or phenyl optionally substituted with at least one R 8 ;
  • R 4 is independently hydrogen; C j -Cg alkyl; or phenyl optionally substituted with at least one R 8 ;
  • R 5 is independently C ] -C 6 alkyl; C r C 6 alkoxy; C j -C 6 haloalkyl; halogen; C 2 -C 8 alkynyl; C r C 6 thioalkyl; phenyl or phenoxy each optionally substituted with at least one R 8 ; cyano; nitro; Cj-C 6 haloalkoxy; C r C 6 haloalkythio; C 2 -C 6 alkenyl; C 2 -C 6 haloalkenyl; acetyl; CO 2 CH 3 ; orN(C r C 2 alkyl) 2 ;
  • R 6 is independently methyl; ethyl; methoxy; methylthio; halogen; or trifluoromethyl;
  • R 7 is independently halogen
  • R 8 is independently halogen; C r C 4 alkyl; C r C 4 alkoxy; C r C 4 haloalkyl; nitro; or cyano; wherein: the amino acid in the first position, based on numbered amino acids from N-terminus to C- terminus, is selected from the group consisting of arginine, lysine, methionine, serine, threonine and tryptophan; the amino acid in the second position, based on numbered amino acids from N-terminus to C-terminus, is selected from the group consisting of arginine, histidine, cysteine, threonine, tyrosine, and tryptophan; and the amino acids in positions three through six, based on numbered amino acids from N- terminus to C-terminus, are any amino acid.
  • compositions comprise hexapeptides wherein the amino acids in the first and second positions of said peptides, based on numbered amino acids from N-terminus to C-terminus, are selected from the group consisting of Arg-Tyr, Arg-Cys, Ser- Thr, Met-Trp, Lys-Trp, Thr-Trp, Trp-Arg, Trp-His, and Trp-Tyr.
  • the peptides may be incorporated into a polymer, including, but not limited to a polysaccharide, a glycol polymer, a polyester, a polyurethane, a polyacrylate, a polyacrylonitrile, a polyamide, a polyolefin, a polystyrene, a vinyl polymer, a polypropylene, silk, a biopolymer, and mixtures thereof.
  • a polysaccharide including, but not limited to a polysaccharide, a glycol polymer, a polyester, a polyurethane, a polyacrylate, a polyacrylonitrile, a polyamide, a polyolefin, a polystyrene, a vinyl polymer, a polypropylene, silk, a biopolymer, and mixtures thereof.
  • compositions comprising the antimicrobial peptides and at least one carrier, including, but not limited to a pharmaceutically acceptable carrier, an industrially acceptable carrier, a household product, and a personal care composition.
  • peptides may be present in an amount of about 0.000001 to about 99% based on the weight percentage of the composition. In some embodiments, the peptides are present in an amount of about 0.001 to about 50% based on the weight percentage of the composition. In other embodiments, the peptides are present in an amount of about 0.01 to about 25% based on the weight percentage of the composition.
  • the carrier may be present in an amount of, for example, about 1 to about 99% based on the weight percentage of said composition. In some embodiments, the carrier is present in an amount of about 50 to about 99% based on the weight percentage of said composition. In other embodiments, the carrier is present in an amount of about 75 to about 99% based on the weight percentage of said composition.
  • the invention also provides methods for preventing, inhibiting, or terminating the growth of at least one microbe comprising administering the antimicrobial peptides and compositions of the invention.
  • the methods are effective against microbes, including, for example, bacteria, archaea, fungi, algae, protozoa, multicellular parasites, and viruses.
  • the methods of the invention are useful against Gram-positive cocci, Gram-negative cocci, Gram-positive straight rods, Gram-negative straight rods, Gram-positive curved rods, Gram-negative curved rods, Gram-positive helical/vibroid rods, Gram- negative helical/vibroid rods, Gram-positive branched rods, Gram-negative branched rods, sheathed bacteria, sulfur-oxidizing bacteria, sulfur or sulfate-reducing bacteria, spirochetes, actinomycetes, myxobacteria, mycoplasmas, rickettsias, chlamydias, cyanobacteria, archea, fungi, parasites, viruses and algae.
  • the methods of the invention are useful against Burkholderia cepacia.
  • the antimicrobial compositions are administered enterally.
  • a dosage may be, for example, about 0.01 to about 100 mg/kg.
  • the antimicrobial compositions are administered parenterally.
  • a dosage may be, for example, about 0.01 to about 100 mg/kg.
  • the antimicrobial compositions are administered topically.
  • a typical dosage may be, for example, about 0.000001 to about 20%o based on the weight of the composition.
  • the antimicrobial compositions are administered to an aqueous environment comprising at least one biofouling microbe.
  • the peptides may be present in an amount of, for example, about 0.001 to about 50% based on the weight percentage of the composition.
  • the antimicrobial compositions of the invention may also be used as coatings for substrates, including, but not limited to personal care products, healthcare products, household products, food preparation surfaces, food packaging surfaces, medical devices, wound dressings, surgical staples, membranes, shunts, surgical gloves, tissue patches, prosthetic devices, wound dranage tubes, blood collection and transfer devices, tracheotomy devices, intraocular lenses, laboratory devices, and textile products.
  • substrates including, but not limited to personal care products, healthcare products, household products, food preparation surfaces, food packaging surfaces, medical devices, wound dressings, surgical staples, membranes, shunts, surgical gloves, tissue patches, prosthetic devices, wound dranage tubes, blood collection and transfer devices, tracheotomy devices, intraocular lenses, laboratory devices, and textile products.
  • the invention also provides substrates coated with the antimicrobial compositions of the invention.
  • Figure 1 is a table demonstrating growth of Burkholderia cepacia in the presence of hexapeptide mixtures comprising equimolar concentrations of peptides with defined L-amino acids ill positions 1 and 2 and undefined (any of the 20 naturally occurring amino acids) in positions 3, 4, 5 and 6.
  • the first column shows the amino acids in the first two positions of each hexapeptide mixture.
  • the second column is the concentration of hexapeptides assayed in parts per million (ppm).
  • the third column is the percent growth inhibition of Burkholderia cepacia by the hexapeptide mixtures at a concentration of 625 ppm.
  • the present invention is directed to peptides possessing antimicrobial activity.
  • Peptides of the present invention may be used to combat microbes which include, but are not limited to, Burkholderia cepacia. These peptides may be used in various environments wherein antimicrobial treatment is desired, such as industrial and clinical settings.
  • the peptides may be made in accordance with any appropriate method.
  • the peptides of the present invention are characterized by specific properties as described below. These properties include, but are not limited to, hydrophobic, cationic and structural characteristics.
  • the peptides of the present invention possess activity toward microbes, especially Burkholderia cepacia, in which activity can be described as "antimicrobial".
  • the term "antimicrobial” is meant to include prevention, inhibition or termination of a microbe.
  • Prevention can be considered to be the obstruction or hindrance of any potential microbial growth.
  • Inhibition can be considered to be a reduction in microbial growth. This may occur via, but is not limited to, a microbiostatic mechanism such as interference in the synthesis of the cell wall or binding to ribosomal subunits to prevent production of microbials proteins.
  • “Termination” can be considered to be actual killing of the microbes by the presence of the composition. This may occur via, but is not limited to, a microbiocidal mechanism such as a change in osmotic pressure leading to bursting of the cell or formation of leaky channels in the cell wall and membrane causing loss of cellular material.
  • microbes is meant to include any organism comprised of the phylogenetic domains bacteria and archaea, as well as unicellular and filamentous fungi (such as yeasts and molds), unicellular and filamentous algae, unicellular and multicellular parasites, and viruses
  • the present invention is effective against bacteria including Gram-positive and Gram- negative cocci, Gram positive and Gram negative straight, curved and helical/vibroid and branched rods, sheathed bacteria, sulfur-oxidizing bacteria, sulfur or sulfate-reducing bacteria, spirochetes, actinomycetes and related genera, myxobacteria, mycoplasmas, rickettsias and chlamydias, cyanobacteria, archea, fungi, parasites, viruses and algae. More specifically, the present invention is useful against Burkholderia cepacia.
  • the Gram-positive and Gram-negative cocci include, but are not limited to, Aerococcus, Enterococcus, Halococcus, Leuconostoc, Micrococcus, Mobiluncus, Moraxella catarrhalis, Neisseria (including N. gonorrheae and N. meningitidis), Pediococcus, Peptostreptococcus, Staphylococcus species (including S. aureus, methicillin-resistant S. aureus, coagulase-negative S. aureus, and S. saprophyticus), Streptococcus species (including S. pyogenes, S. agalactiae, S. bovis, S. pneumoniae, S.
  • the Gram-positive and Gram-negative straight, curved, helical/vibrioid and branched rods include, but are not limited to, Acetobacter, Acinetobacter, Actinobacillus equuli, Aeromonas, Agrobacterium, Alcaligenes, Aquaspir ilium, Arcanobacterium haemolyticum, Bacillus species (including B. cereus and B. antliracis), Bacteroides species (including B. fragilis), Bartonella, Bordetella species (including B. pertussis), Brochothrix, Brucella, Burkholderia cepacia, Calymmatobacterium granulomatis, Campylobacter species (including C.
  • Capnocytophaga Caulobacter, Chromobacterium violaceum, Citrobacter, Clostridium species (including C. perfringens, C. tetani and C. difficile), Com ⁇ mon ⁇ s, Curtobacterium, Edwardsiella, Eikenella, Enterobacter, Erwinia, Erysipelothrix, Escherichia species (including E. coli), Flavobacterium species (including E. meninosepticum), Francisella species (including E. tularensis), Fusobacterium (including F. nucleatum), Gardnerella species (including G. vaginalis), Gluconobacter, Haemophilus species (including H. influenzae and H.
  • ducreyi Hafnia, Helicobacter (including H.pylori), Herpetosiphon, Klebsiella species (including K. pneumoniae), Kluyvera, Lactobacillus, Legionella species (including L. pneumophila), Leptotrichia, Listeria species (including L. monocytogenes), Microbacterium, Morganella, Nitrobacter, Nitrosomonas, Pasteurella species (including P. multocida), Pectinatus, Porphyromonas gingivalis, Proteus species (including P. mirabilis), Providencia, Pseudomonas species (including P. aeruginosa, P. mallei, P. pseudomallei and P.
  • solan acearum solan acearum
  • Rahnella Renibacterium salmoninarum
  • Salmonella Serratia, Shigella, Spirillum, Streptobacillus species (including S. moniliformis), Vibrio species (including V. cholerae and V. vulnificus), Wolinella, Xanthobacter, Xenorhabdus, Yersinia species (including Y. pestis and Y. enter ocolitica), Zanthomonas and Zymomonas.
  • the sheathed bacteria include, but are not limited to, Crenothrix, Leptothrix and Sphaerotilus.
  • the sulfur-oxidizing bacteria include, but are not limited to, Beggiatoa, Gallionella, Sulfolobus, Thermothr-ix, Thiobacillus species (including J. ferroxidans), Thiomicrospira and Thiosphaera.
  • the sulfur or sulfate-reducing bacteria include, but are not limited to, Desulfobacter, Desulfobulbus, Desulfococcus, Desulfomonas, Desulfosarcina, Desulfotomaculum, Desulfovibrio and Desulfuromonas.
  • the spirochetes include, but are not limited to, Treponema species (including J. pallidum, T. per pneumonia, T. hyodysenteriae and J. denticola), Borrelia species (including B. burgdorferi and B. recurrentis), Leptospira and Serpulina.
  • the actinomycetes and related genera include, but are not limited to, Acetobacterium, Actinomyces species (including A. israelii), Bifidobacterium, Brevibacterium, Corynebacterium species (including C. diphtheriae, C. insidiosum, C. michiganese, C. rathayi, C. sepedonicum, C. nebraskense), Dermatophilus, Eubacterium, Mycobacterium species (including M. tuberculosis and M. leprae), Nocardia, Propionibacterium, Rhodococcus and Streptomyces.
  • the rnyxobacteria include, but are not limited to, Chondromyces, Cystobacter, Melittangium, Myxococcus, Nannocystis, Polyangium and Stigmatella.
  • the mycoplasmas include, but are not limited to, Mycoplasma species (including M. pneumoniae), Mycoplasma- like organisms of plants and invertebrates, Spiroplasma and Ureaplasma species (including U. urealyticum).
  • the rickettsias and chlamydias include, but are not limited to, Aegyptianella, Anaplasma, Chlamydia species (including C. pneumoniae, C. trachomatis and C. psittaci), Cowdria, Coxiella, Ehrlichia, Eperythrozoon, Haemobartonella, Neorickettsia, Rickettsia and Rickettsiella.
  • the cyanobacteria include, but are not limited to, Anabaena, Nostoc, Oscillatoria, Pleurocapsa, Prochloron and Synechococcus.
  • the archea include, but are not limited to, all methanogens (Methanobacterium, Methanobrevibacter, Methanococcoides, Methanococcus, Methanogenium, Methanolobus, Methanomicrobium, Methanoplanus, Methanosarcina, Methanospir ilium, Methanothermus and Methanothrix), and the genera Acidianus, Archaeoglobus, Desulfurococcus, Haloarcula, Halobacterium, Halococcus, Haloferax, Natronobacterium, Natronococcus, Pyrococcus, Pyrodictium, Staphylothermus, Sulfolobus, Thermococcus, Thermophila, Thermoplasma and Thermoproteus.
  • methanogens Methanobacterium, Methanobrevibacter, Methanococcoides, Methanococcus, Methanogenium, Methanolobus, Methanomicrobium,
  • the present invention may also be used against fungi which include, but are not limited to, Acremonium, Aspergillus, Blastomyces species (including B. dermatitidis), Candida species (including C. albicans), Ceratocystis, Chaetomium, Coccidioides species (including C. immitis), Cryptococcus neoformans, Epidermophyton, Fusarium species (including E. oxysporum), Gongronella, Histoplasma species (including H.
  • fungi include, but are not limited to, Acremonium, Aspergillus, Blastomyces species (including B. dermatitidis), Candida species (including C. albicans), Ceratocystis, Chaetomium, Coccidioides species (including C. immitis), Cryptococcus neoformans, Epidermophyton, Fusarium species (including E. oxysporum), Gongronella, Histoplasma species (including H
  • capsulatum capsulatum
  • Hormonea Malassezia furfur, Microsporum, Mycosphaerellafijiensis, Paracoccidiodes brasiliensis, Penicillium, Pneumocystis carinii, Pythium, Rhizoctonia, Rhodotorula, Saccharomyces, Sporoihrix schenckii, Torula, Trichoderma, Trichophyton species (including J. mentagrophytes and J. rubrum) and Trichothecium.
  • the present invention may be used against parasites which include, but are not limited to, Acanthamoeba species, Ascaris lumbricoides, Babesia, Balamuthia, Balantidium, Blastocystis species including B. hominis, Chilomastix, Clonorchis sinensis, Cryptosporidium parvum, Cyclospora, Dientamoebafragilis, Diphyllobothrium, Echinococcus, Endolimax, Entamoeba species (including E. histolytica), Enterobius species (including E.
  • Trichomonas vaginalis Trichomonas vaginalis
  • Trichuris species including J. trichiura, Trypanosoma, Dirofilaria, Brugia, Wuchereria, Vorticella, Eimeria species, Hexamita species and Histomonas meleagidis.
  • the present invention may also be used against viruses which include, but are not limited, to adenovirus, arborviruses (including hanta virus), astrovirus, coronavirus, cytomegalovirus, enteroviruses (including coxsackievirus A), ⁇ pstein-Barr virus, hepatitis A virus, hepatitis B virus, herpes viruses (including herpes simples virus or ⁇ SN), human immunodeficiency virus ( ⁇ IN), human papilloma virus, human T-cell leukemia virus, influenza virus, mumps virus, ⁇ orwalk viruses, orbivirus, parainfluenzae viruses, parvovirus B19, poxviruses, Rabies virus, respiratory syncytial virus, rhinovirus, rotavirus, Rubella virus, varicella-zoster virus, vesicular stomatitis virus, cauliflower mosaic virus, cowpea mosaic virus, cowpox virus and rabbit myxomatis virus.
  • viruses include, but
  • the present invention may be used against algae which include, but are not limited to, Chlorella, Fragilaria, Gomphonema, Navicula, Nitzschia, Pfiesteria (dinoflagellate), Scenedesmus, Skeletoneona and Ulothrix.
  • diseases caused by, but not limited to, bacteria, fungi, viruses and parasites in.animals, plants, avian and aquatic organisms include abscesses, bacteremia, contamination of peritoneal dialysis fluid, endocarditis, pneumonia, meningitis, osteomyelitis, cellulitis, pharyngitis, otitis media, sinusitis, scarlet fever, arthritis, urinary tract infection, laryngotracheitis, erysipeloid, gas gangrene, tetanus, typhoid fever, acute gastroenteritis, bronchitis, epiglottitis, plague, sepsis, chancroid, wound and burn infection, cholera, glanders, periodontitis, genital infections, empyema, granuloma inguinale, Legionnaire's
  • swine erysipelas peritonitis, abortion, encephalitis, anthrax, nocardiosis, pericarditis, mycetoma, peptic ulcer, melioidosis, Haverhill fever, tularemia, Moko disease, galls (such as crown, cane and leaf), hairy root, bacterial rot, bacterial blight, bacterial brown spot, bacterial wilt, bacterial fin rot, dropsy, columnaris disease, pasteurellosis, furunculosis, enteric redmouth disease, vibriosis offish, fouling of medical devices.
  • Peptides of the present invention may also be useful in treating diseases caused by spirochetes including syphilis, yaws, Lyme disease, Weil's disease, meningitis, leptospirosis, tick- and louse-borne relapsing fever, tick spirochetosis and canine, avian, rodent or lagomorph borreliosis.
  • diseases caused by actinomycetes may be treatable by the present invention including tuberculosis, leprosy, cervicofacial lesions, abdominal lesions, thoracic lesions, pulmonary lesions and lesions of other organs, leafy gall and fish corynebacteriosis.
  • Treatable rickettsial and chlamydial diseases or infections by the present invention include psittacosis, boutonneuse fever, ehrlichiosis, typhus fever, murine typhus, Brill's disease, Rocky Mountain spotted fever, Q fever, rickettsial pox, lymphogranuloma venereum, urethritis and trachoma. Treatable diseases or infections by mycoplasma include lethal yellowing.
  • Fungal infections treatable by the present invention include oral, cutaneous and vaginal thrush, cryptococcosis, superficial mycosis (including Athlete's foot), subcutaneous mycosis (including sporotrichosis), systemic mycosis (including histoplasmosis and coccidioidomycosis), Farmer's lung, aflatoxin disease, histoplasmosis, pneumonia, endocardititis, burn infections, mucormycosis, pityriasis versicolor, fungemia due to indwelling catheter infections, damping off, rot, panama disease, black leaf streak, anthracnose, apple scab, black knot, rust, canker, gray mold, blue mold, blight, powdery and downy mildew, wilt, damping off and leaf spot.
  • Viral infections treatable by the present invention include common colds, hemorrhagic fevers, mononucleosis, genital disease, keratoconjunctivitis, encephalitis, neonatal HSV, mucocutaneous HSV, chicken pox, retinitis, AIDS, influenza, pneumonia, bronchiolitis, genital papilloma, measles (including German measles), rabies, rubella, mumps, shingles, poliomyelitis, viral diarrhea, yellow fever, zoster, roseola, laryngotracheobronchitis, gastroenteritis, hepatitis (including hepatitis A and B), dengue fever, orf virus infection, moUuscum contagiosum virus infection, fruit and vegetable mosaic viruses, tobacco ringspot virus, leaf curl virus, dropsy, cauliflower disease and necrotic viruses offish.
  • Parasitic infections treatable by the present invention include trichinosis, schistosomiasis, malaria, giardiasis, amoebiasis, encephalitis, keratitis, gastroenteritis, urogenital infections, toxoplasmosis, African sleeping sickness, white spot disease, slimy skin disease, chilodonella, costia, hexamitiasis, velvet and coral fish disease.
  • Peptides of the present invention are also useful as infection or inflammation seeking agents or as T-cell activators. More preferably, peptides of the present invention are useful in the treatment of infections in respiratory disorders including cystic fibrosis, pneumonia or bacterial bronchitis.
  • the peptide sequences may be selected from synthetic combinatorial libraries using methods known to one of ordinary skill in the art to produce a mixture of peptides or a single peptide within a mixture with optimal activity for a target application.
  • the peptide mixtures may be selected from an L-hexapeptide library comprised of equimolar concentrations of all peptides.
  • the amino acids comprising the peptides are selected from all of the naturally occurring amino acids, as well as non-natural amino acids.
  • the present invention is useful in a variety of environments including industrial, clinical, the household, and personal care.
  • the peptide compositions of the present invention for industrial, pharmaceutical, household and personal care use may comprise at least one active ingredient, of which the peptide mixture of the present invention is an active ingredient acting alone, additively, or synergistically against the target microbe.
  • the peptide mixtures of this invention may be delivered in a form suitable for use in environments including industry, pharmaceutics, household, and personal care.
  • the peptides of the present invention are preferably soluble in water and may be applied or delivered with an acceptable carrier system.
  • the composition may be applied or delivered with a suitable carrier system such that the active ingredient may be dispersed or dissolved in a stable manner so that the active ingredient, when it is administered directly or indirectly, is present in a form in which it is available in a particularly advantageous way.
  • the separate components of the peptide compositions of the present invention may be preblended or each component may be added separately to the same environment according to a predetermined dosage for the purpose of achieving the desired concentration level of the treatment components and so long as the components eventually come into intimate admixture with each other.
  • the present invention may be administered or delivered on a continuous or intermittent basis.
  • the peptide mixtures of the present invention when present in a composition will preferably be present in an amount of about 0.000001% to about 100%, more preferably from about 0.001%) to about 50%, and most preferably from about 0.01% to about 25%).
  • compositions of the present invention comprising peptide mixtures of the present invention
  • the composition when a carrier is present, the composition comprises preferably from about 50% to about 99%, more preferably from about 25% to about 99%, and most preferably from about 1% to about 99%) by weight of at least one carrier.
  • the present invention and any suitable carrier may be prepared for delivery in forms including solution, microemulsion, suspension or aerosol.
  • Generation of the aerosol or any other means of delivery of the present invention may be accomplished by any of the methods known in the art.
  • the antimicrobial composition is supplied in a finely divided form along with any suitable carrier with a propellant.
  • Liquified propellants are typically gases at ambient conditions and are condensed under pressure.
  • the propellant may be any acceptable and known in the art including propane and butane, or other lower alkanes, such as those of up to 5 carbons.
  • the antimicrobial composition is held within a container with an appropriate propellant and valve, and maintained at elevated pressure until released by action of the valve.
  • compositions may be prepared in a conventional form suitable for, but not limited to topical or local application such as an ointment, paste, gel, spray and liquid, by including stabilizers, penetrants and the carrier or diluent with peptide according to a known technique in the art. These preparations may be prepared in a conventional form suitable for enteral, parenteral, topical or inhalational applications.
  • the present invention may be used in compositions suitable for household use.
  • compositions of the present invention are also useful as an active antimicrobial ingredient in household products such as cleansers, detergents, astringents, disinfectants, dishwashing liquids, and soaps.
  • the antimicrobial composition of the present invention may be delivered in an amount and form effective for the prevention, removal or tennination of microbes.
  • the antimicrobial composition for household use may be defined as comprising at least one peptide mixture of the present application and at least one suitable carrier.
  • the composition comprises from about 0.00001% to about 50%), more preferably from about 0.0001% to about 25%, most preferably from about 0.0005% to about 10% by weight of peptide mixture based on the weight percentage of the total composition.
  • the present invention may further be used in hygiene compositions for personal care.
  • compositions of the present invention are useful as an active ingredient in personal care products such as facial cleansers, astringents, body wash, shampoos, conditioners, cosmetics and other hygiene products.
  • the hygiene composition may comprise any carrier or vehicle known in the art to obtain the desired form (such as solid, liquid, semisolid or aerosol) as long as the effects of the peptide mixture of the present invention are not impaired.
  • Methods of preparation of hygiene compositions are not described herein in detail, but are known in the art. For its discussion of such methods, THE CTFA COSMETIC INGREDIENT HANDBOOK, Second Edition, 1992, and pages 5-484 of A FORMULARY OF COSMETIC PREPARATIONS (Vol. 2, Chapters 7-16) are incorporated herein by reference.
  • the hygiene composition for use in personal care may be defined as comprising at least one peptide mixture of the present application and at least one suitable carrier.
  • the composition comprises from about 0.00001%) to about 50%>, more preferably from about 0.0001% to about 25%, most preferably from about 0.0005% to about 10% by weight of peptide mixture based on the weight percentage of the total composition.
  • the peptide mixtures of the present invention may be used in industry. In the industrial setting, the presence of microbes can be problematic, as microbes are often responsible for industrial contamination and biofouling.
  • Antimicrobial compositions for industrial applications comprise an effective amount of the peptide mixtures of the present invention in an antimicrobial composition for industrial use with at least one acceptable carrier or vehicle known in the art to be useful in the treatment of such systems.
  • Such carriers or vehicles may include diluents, deflocculating agents, penetrants, spreading agents, surfactants, suspending agents, wetting agents, stabilizing agents, compatability agents, sticking agents, waxes, oils, co-solvents, coupling agents, foams, antifoaming agents, natural or synthetic polymers, elastomers and synergists.
  • Methods of preparation, delivery systems and carriers for such antimicrobial compositions are not described here in detail, but are known in the art. For its discussion of such methods, U.S. Patent No. 5,939,086 is herein incorporated by reference.
  • the preferred amount of antimicrobial composition to be used may vary according to the peptide mixture and situation in which the composition is being applied.
  • the antimicrobial compositions of the present invention may be useful in nonaqueous environments.
  • Such nonaqueous environments may include, but are not limited to, terrestrial environments, dry surfaces or semi-dry surfaces in which the antimicrobial composition is applied in a manner and amount suitable for the situation.
  • the antimicrobial compositions of the present invention may also be used to form contact-killing coatings or layers on a variety of substrates including personal care products (such as toothbrushes, contact lens cases and dental equipment), healthcare products, household products, food preparation surfaces and packaging, and laboratory and scientific equipment.
  • substrates include medical devices such as catheters, urological devices, blood collection and transfer devices, tracheotomy devices, intraocular lenses, wound dressings, sutures, surgical staples, membranes, shunts, gloves, tissue patches, prosthetic devices (e.g., heart valves) and wound drainage tubes.
  • other substrates include textile products such as carpets and fabrics, paints and joint cement.
  • the peptides may also be incorporated into polymers, such as polysaccharides (cellulose, cellulose derivatives, starch, pectins, alginate, chitin, guar, carrageenan), glycol polymers, polyesters, polyurethanes, polyacrylates, polyacrylonitrile, polyamides (e.g., nylons), polyolefins, polystyrenes, vinyl polymers, polypropylene silks or biopolymers.
  • the peptides may be conjugated to any polymeric material with the following specified functionality: 1) carboxy acid, 2) amino group, 3) hydroxyl group and/or 4) haloalkyl group.
  • the antimicrobial composition for treatment of nonaqueous environments may be defined as comprising at least one peptide mixture of the present application and at least one suitable carrier.
  • the composition comprises from about 0.001% to about 75%, more preferably from about 0.01 to about 50%>, most preferably from about 0.1 % to about 25% by weight of peptide mixture based on the weight percentage of the total composition.
  • the antimicrobial compositions of the present invention may be useful in aqueous environments.
  • “Aqueous environments” as used herein, is meant to include any type of system containing water, including but not limited to, natural bodies of water such as lakes or ponds; artificial, recreational bodies of water such as swimming pools; and drinking reservoirs such as wells.
  • the antimicrobial compositions of the present invention are useful in treating microbial growth in these aqueous environments and may be applied at or near the surface of water.
  • the antimicrobial composition for treatment of aqueous environments may be defined as comprising at least one peptide mixture of the present application and at least one suitable carrier.
  • the composition comprises from about 0.001% to about 50%, more preferably from about 0.003% to about 15%>, most preferably from about 0.01% to about 5% by weight of peptide mixture based on the weight percentage of the total composition.
  • the composition of the present invention may be administered for clinical use, in a therapeutically effective amount and composition, to beings infected with a microorganism discussed above. Beings treatable clinically include all land, air and water animals, and plants, but preferably mammals and most preferably humans.
  • the composition may be administered prophylactically.
  • the therapeutic and prophylactic dose for the present invention may vary according to several factors including the age, weight, and condition of the individual, route of administration and/or other drug interactions. The principles and factors for determining dosage are not discussed here in detail, but are known in the art and may be referenced in pages 1-83 of GOODMAN AND GILMAN'S THE PHARMACOLOGICAL BASIS OF THERAPEUTICS (8th Edition).
  • the preferred doses for therapeutic and prophylactic treatment may vary and can be adjusted to suit the individual and situation.
  • the therapeutically and prophylactically effective amount is preferably from about 0.5 mg/kg to about 100 mg/kg, more preferably from about 1 mg/kg to about 20 mg/kg, and most preferably from about 2 mg/kg to about 10 mg/kg.
  • the present invention also provides a process for the production of a pharmaceutical composition.
  • Such process comprises bringing at least one of the individual components described thereof into intimate admixture with a peptide mixture of the present invention, and when required, compounding the obtained composition in unit dosage form, for example filling said composition into gelatin, e.g., soft or hard gelatin, capsules.
  • gelatin e.g., soft or hard gelatin, capsules.
  • the pharmaceutical composition may be defined as comprising at least one peptide mixture of the present application and at least one suitable carrier.
  • the composition comprises from about 0.000001% to about 75%), more preferably from about 0.00001%> to about 25%), most preferably from about 0.0001% to about 12% by weight of peptide mixture based on the weight percentage of the total composition.
  • the pharmaceutical composition may be administered for treatment of any land, air or water animal potentially having or having at least one microbial infection. Treatment of an animal with the present invention may also include prophylactic treatment.
  • the mode of administration is such as to deliver a binding inhibiting effective amount of the pharmaceutical composition to the site of infection.
  • therapeutic delivery of the pharmaceutical composition may be achieved via enteral administration, which includes oral, sublingual and rectal administration, or via parenteral administration, which includes intramuscular, intravenous and subcutaneous admimstration.
  • therapeutic delivery of the pharmaceutical composition may also be achieved via other routes including topical and inhalational. As discussed above, preferred dosage ranges will vary according to the individual and situation.
  • Enteral administration of the pharmaceutical composition is preferably administered at a dosage of from about 0.01 mg/kg to about 100 mg/kg, more preferably from about 2 mg/kg to about 50 mg/kg, and most preferably from about 5 mg/kg to about 30 mg/kg.
  • Parenteral administration of the pharmaceutical composition is preferably admimstered at a dosage from about 0.01 mg/kg to about 100 mg/kg, more preferably from about 1 mg/kg to about 30 mg/kg, and most preferably from about 5 mg/kg to about 25 mg/kg.
  • Topical administration of the pharmaceutical composition is preferably administered at a dosage from about 0.000001% to about 20%>, more preferably from about 0.001% to about 15%), and most preferably from about 0.025% to about 10%.
  • Inhalational administration of the pharmaceutical composition is preferably administered at a dosage from about 0.0001 mg to about 25 mg, more preferably from about 0.01 mg to about 15 mg, and most preferably from about 0.1 mg to about 10 mg.
  • peptide mixtures of this invention may be delivered in a pharmaceutically acceptable composition suitable for any of the routes of administration discussed above.
  • “Pharmaceutically acceptable” is used herein to refer to those materials which are within the scope of sound medical judgement, suitable for use in contact with the tissue of humans and lower animals, avian and aquatic organisms without undue toxicity, irritation, allergic response and the like commensurate with a reasonable benefit/risk ratio, and effective for their intended use in the composition.
  • the pharmaceutical compositions may include, but are not limited to, at least one acceptable carrier.
  • the carrier is generally an inert bulk agent added to make the active ingredients easier to handle and can be solid, semisolid or liquid in the usual manner as well as understood in the art.
  • a carrier may be a solvent, diluent or carrier comprising of waxes, cellulose derivatives, mineral oils, vegetable oils, petroleum derivatives, water, anhydrous lanolin, white petrolatum, liquid petrolatum, olive oil, ethanol and ethanol-polysorbate 80 solutions, propylene glycol- water solutions, and jojoba oils, methylcellulose or paraffin, beeswax, glyceryl stearate, PEG-2 stearate, propylene glycol stearate, glycol stearate, cetyl alcohol, stearyl alcohol, and any mixture thereof.
  • Carriers used may include commercially available carriers or vehicles including Aquaphor ® ointment base (Beirsdorf Inc.), Eucerin ® creme/lotion (Beirsdorf), Acid Mantle ® (Sandoz), Nutraderm ® creme/lotion (Owen), Vehicle/N ® or Vehicle/N ® Mild (Neutrogena).
  • Aquaphor ® ointment base Beirsdorf Inc.
  • Eucerin ® creme/lotion Beirsdorf
  • Acid Mantle ® Sandoz
  • Nutraderm ® creme/lotion Owen
  • Vehicle/N ® or Vehicle/N ® Mild Netrogena
  • phrases of the invention may also include any delivery vehicle or device known in the art to enhance the transport of peptides across tissue and/or cell surfaces to reach the circulatory system and/or target site.
  • delivery vehicles or devices may include liposomes or immunogenic liposomes, which may be adminstered in admixture with any carrier (discussed above) with regard to the intended route of administration, and standard pharmaceutical practice.
  • Dosages of peptide mixtures associated with such delivery vehicles or devices will vary according to certain factors including the age, weight, and condition of the individual, as well as the pharmacokinetics and release characteristics of the peptides from the delivery vehicles or devices.
  • the ratio of peptide mixture to liposome and carrier will depend on the chemical nature, solubility, trapping efficiency, and stability of the peptides, as well as the dosage anticipated. Maximal delivery of the peptides of the present invention may be accomplished by varying the lipid:peptide ratio as well as the type of peptide and liposome used.
  • the present invention also provides a process for the production of an antibiofouling composition for industrial use.
  • Such process comprises bringing at least one of any industrially acceptable carrier known in the art into intimate admixture with a peptide mixture of the present invention.
  • the carrier may be any suitable carrier discussed above or known in the art.
  • the suitable antibiofouling compositions may be in any acceptable form for delivery of the composition to a site potentially having, or having, at least one living microbe.
  • the antibiofouling compositions may be delivered with at least one suitably selected carrier as hereinbefore discussed using standard formulations.
  • the mode of delivery may be such as to have a binding inhibiting effective amount of the antibiofouling composition at a site potentially having, or having at least one living microbe.
  • the antibiofouling compositions of the present invention are useful in treating microbial growth that contributes to biofouling, such as scum or slime formation, in these aqueous environments.
  • the antibiofouling composition may be delivered in an amount and form effective for the prevention, removal or termination of microbes.
  • the antibiofouling composition of the present invention preferably comprises at least one peptide mixture of the present application from about 0.001% to about 50%, more preferably from about 0.003%> to about 15%>, most preferably from about 0.01% to about 5%> by weight of peptide mixture based on the weight percentage of the total composition.
  • the amount of antibiofouling composition is preferably delivered in an amount of about 1 mg/1 to about 1000 mg/1, more preferably from about 2 mg/1 to about 500 mg/1, and most preferably from about 20 mg/1 to about 140 mg/1.
  • the peptides of the present invention may be modified at the N- and/or C-terminus.
  • Modifications as used herein include modifications at the N-terminus and/or C-terminus or modification of any position on at least one amino acid residue.
  • the modified peptides may be represented by Formulae I and II:
  • Rj is C r C 20 alkyl; C 3 -C 6 cycloalkyl; C 4 -C 20 alkenyl; C 4 -C 20 alkynyl; C 1 -C 20 haloalkyl; C 3 -C 20 haloalkenyl; C 3 -C 20 haloalkynyl; C 2 -C 20 alkoxyalkyl; C 2 -C 20 alkylthioalkyl; C 2 -C 20 alkylsulfinylalkyl; C 2 -C 20 alkylsulfonylalkyl; C 5 -C 20 cycloalkylalkyl; C 4 -C 20 alkenyloxyalkyl; C 4 -C 20 alkynyloxyalkyl; C 4 -C 20 (cycloalkyl)oxyalkyl; C 4 -C 20 alkenylthioalkyl; C 4 -C 20 alkynylthioalkyl;
  • R 2 is C r C 20 alkyl; C 3 -C 6 cycloalkyl; C 4 -C 20 alkenyl; C 4 -C 20 alkynyl; Cj-C 20 haloalkyl; C 3 -C 20 haloalkenyl; C 3 -C 20 haloalkynyl; C 2 -C 20 alkoxyalkyl; C 2 -C 20 alkylthioalkyl; C 2 -C 20 alkylsulfinylalkyl; C 2 -C 20 alkylsulfonylalkyl; C 5 -C 20 cycloalkylalkyl; C 4 -C 20 alkenyloxyalkyl; C 4 -C 20 alkynyloxyalkyl; C 4 -C 20 (cycloalkyl)oxyalkyl; C 4 -C 20 alkenylthioalkyl; C 4 -C 20 alkynylthioalkyl; C
  • R 3 is independently hydrogen; C r C 4 alkyl; or phenyl optionally substituted with at least one
  • R 4 is independently hydrogen; C C 8 alkyl; or phenyl optionally substituted with at least one R 5 is independently C r C 6 alkyl; C C 6 alkoxy; - haloalkyl; halogen; C 2 -C 8 alkynyl; C r C 6 thioalkyl; phenyl or phenoxy each optionally substituted with at least one R 8 ; cyano; nitro; C r C 6 haloalkoxy; C C 6 haloalkythio; C 2 -C 6 alkenyl; C 2 -C 6 haloalkenyl; acetyl; CO 2 CH 3 ; or N( -C 2 alkyl) 2 ;
  • R 6 is independently methyl; ethyl; methoxy; methylthio; halogen; or trifluoromethyl;
  • R 7 is independently halogen
  • R 8 is independently halogen; C--C 4 alkyl; C C 4 alkoxy; C r C 4 haloalkyl; nitro; or cyano.
  • hydrocarbyl is defined by Rj and R 2 .
  • alkyl used either alone or in compound words such as “alkylthio,” “haloalkyl,” or “alkylthioalkyl” denotes straight-chain or branched alkyl; e.g., methyl, ethyl, n-propyl, i-propyl, or the different butyl, pentyl, hexyl, etc. isomers.
  • Cycloalkyl denotes cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • cycloalkyloxyalkyl denotes the cycloalkyl groups linked through an oxygen atom to an alkyl chain. Examples include cyclopentyloxymethyl and cyclohexyloxybutyl.
  • cycloalkylthioalkyl are the cycloalkyl groups linked through a sulfur atom to an alkyl chain; e.g., cyclopropylthiopentyl.
  • Cycloalkylalkyl denotes a cycloalkyl ring attached to a branched or straight-chain alkyl; e.g., cyclopropylmethyl and cyclohexylbutyl.
  • Cycloalkylalkyl denotes a cycloalkyl ring attached to a branched or straight-chain alkyl; e.g., cyclopropylmethyl and cyclohexylbutyl.
  • Alkenyl denotes straight chain or branched alkenes; e.g. , 1-propenyl, 2-propenyl, 3- propenyl and the different butenyl, pentenyl, hexenyl, etc. isomers. Alkenyl also denotes polyenes such as 1,3-hexadiene and 2,4,6-heptatriene.
  • Alkenyl also denotes polyenes such as 1,3-hexadiene and 2,4,6-heptatriene.
  • Alkenyl also denotes polyenes such as 1,3-hexadiene and 2,4,6-heptatriene.
  • Alkenyl denotes straight chain or branched alkynes; e.g. , ethynyl, 1-propynyl, 3-propynyl and the different butynyl, pentynyl, hexynyl, etc. isomers.
  • Alkoxy denotes methoxy, ethoxy, n-propyloxy, isopropyloxy and the different butoxy, pentoxy, hexyloxy, etc. isomers.
  • Alkoxy alkenyl and alkoxyalkynyl denoted groups in which the alkoxy group is bonded through the oxygen atom to an alkenyl or alkynyl group, respectively. Examples include CH 3 OCH 2 CH ⁇ CH and (CH 3 ) D CHOCH 2 C ⁇ CCH 2 .
  • alkenyloxyalkyl denotes groups in which the alkenyloxy moiety is attached to an alkyl group.
  • H 2 C CHCH 2 OCH 2 CH 2
  • H 2 C CHCH 2 OCH(CH 3 )CH 2
  • alkenylthioalkyl denotes the alkenylthio moieties bonded to an alkyl group.
  • Alkynyloxy denotes straight or branched alkynyloxy moieties. Examples include HC ⁇ CCH 2 O, CH 3 C ⁇ CCH 2 O and CH 3 C ⁇ CCH 2 CH 2 O.
  • Alkynyloxyalkyl denotes alkynyloxy moieties bonded to alkyl groups; e.g., CH 3 C ⁇ CCH 2 OCH 2 CH 2 and HC ⁇ CCH 2 OCH(CH 3 )CH 2 .
  • Alkynylthioalkyl denotes alkynylthio moieties bonded to alkyl groups. Example include CH 3 C ⁇ CCH 2 SCH 2 CH 2 and CH 3 CsCCH 2 CH 2 SCH(CH 3 )CH 2 .
  • Alkylthio denotes methylthio, ethylthio, and the different propylthio, butylthio, pentylthio and hexylthio isomers.
  • Alkylthioalkyl denotes alkylthio groups attached to an alkyl chain; e.g., CH 3 CH 2 SCH 2 CH(CH 3 ) and (CH 3 ) 2 CHSCH 2 .
  • Alkylsulfmyl denotes both enantiomers of an alkylsulfinyl group. For example, CH 3 S(O), CH 3 CH 2 S(O), CH 3 CH 2 CH 2 S(O), (CH 3 ) 2 CHS(O) and the different butylsulfinyl, pentylsulfmyl and hexylsufinyl isomers.
  • Alkylsulfinylalkyl denotes alkylsulfinyl groups attached to an alkyl chain; e.g., CH 3 CH 2 S(O)CH 2 CH(CH 3 ) and (CH 3 ) 2 CHS(O)CH 2 .
  • alkylsulfonyl examples include CH 3 S(O) 2 , CH 3 CH 2 S(O) 2 , CH 3 CH 2 CH 2 S(O) 2 , (CH 3 ) 2 CHS(O) 2 and the different butylsulfonyl, pentylsulfonyl and hexylsulfonyl isomers.
  • Alkylsulfonylalkyl denotes alkylsulfonyl groups attached to an alkyl chain; e.g., CH 3 CH 2 S(O) 2 CH 2 CH(CH3) and (CH 3 ) 2 CHS(O) 2 CH 2 .
  • halogen either alone or in compound words such as “haloalkyl”, denotes fluorine, chlorine, bromine or iodine. Further, when used in compound words such as “haloalkyl", said alkyl may be partially or fully substituted with halogen atoms which may be the same or different.
  • haloalkyl include F 3 C, C1CH 2 , CF 3 CH 2 and CF 3 CF 2 .
  • Haloalkenyloxyalkyl denotes haloalkenyl groups bonded to oxygen and in turn bonded to alkyl groups.
  • Examples of "haloalkynyl” include HC ⁇ CCHCl, CF 3 C ⁇ C, CC1 3 C ⁇ C and FCH 2 C ⁇ CCH 2 .
  • Haloalkynyloxyalkyl denotes haloalkynyl groups bonded through an oxygen atom to an alkyl moiety. Examples include CF 3 C ⁇ CCH 2 OCH 2 CH 2 , ClCH 2 C ⁇ CCH 2 CH 2 OCH(CH 3 ), etc.
  • haloalkoxy include CF 3 O, CCl 3 CH 2 O, CF 2 HCH 2 CH 2 O and CF 3 CH 2 O.
  • Haloalkoxyalkyl denotes haloalkoxy groups bonded to straight-chain or branched alkyl groups; e.g., CF 2 HCH 2 CH 2 OCH 2 CH 2 , CCl 3 CH 2 OCH(CH 3 ) and CF 3 OCH 2 .
  • Trialkylsilyl designates a group with three alkyl groups bonded to silicon; e.g., (CH 3 ) 3 Si and t-Bu(CH 3 ) 2 Si.
  • “Trialkylsilylalkyl” denotes trialkylsilyl groups bonded to another straight-chain or branched alkyl group. Examples include (CH 3 ) 3 SiCH 2 and t-Bu(CH 3 ) 2 SiCH 2 CH(CH 3 )CH 2 .
  • C-C,- " prefix where i and j are numbers from 1 to 10.
  • C- -C 3 alkylsulfonyl designates methylsulfonyl through propylsulfonyl
  • C 2 alkoxyalkoxy designates CH 3 OCH 2 O
  • C 3 alkoxyalkoxy designates, for example, CH 3 OCH 2 CH 2 O or CH 3 CH 2 OCH 2 O
  • C 4 alkoxyalkoxy designates the various isomers of an alkoxy group substituted with a second alkoxy group containing a total of 4 carbon atoms, examples including CH 3 CH 2 CH 2 OCH 2 O, and CH 3 CH 2 OCH 2 CH 2 O.
  • alkoxyalkyl include CH 3 OCH 2 , CH 3 OCH 2 CH 2 , CH 3 CH 2 OCH 2 , CH 3 CH 2 CH 2 CH 2 OCH 2 and CH 3 CH 2 OCH 2 CH 2 .
  • the -NH 2 group (Formula I) or the -NH-R 2 group (Formula II) is bound to the carbon of the alpha carboxyl group of the C-terminal amino acid.
  • R j comprises from about 5 to about 15 carbon atoms, and more preferably comprises from about 6 to about 11 carbon atoms.
  • Rj comprises an alkyl group having from about 1 to about 20 carbon atoms.
  • the alkyl group comprises from about 5 to about 15 carbon atoms, and more preferably comprises from about 6 to about 11 carbon atoms.
  • R 2 comprises 5 to 15 carbon atoms, and more preferably from about 6 to about 11 carbon atoms.
  • R 2 comprises hydrogen, or R 2 comprises an alkyl group.
  • R 2 is an alkyl group, preferably R 2 comprises from about 5 to about 15 carbon atoms, and more preferably from about 6 to about 11 carbon atoms.
  • Peptides of the present invention may comprise residues from any of the 20 natural amino acids. These natural amino acids may be in the D or L configuration. The terms D and L are used herein as they are known to be used in the art. In addition, modified peptides of the present invention may also comprise a monomer or dimer.
  • the amino acids of the peptides of the present invention may also be modified.
  • the carboxyl group on the C-terminal end of the peptide may be esterified with an alkyl, substituted alkyl, alkene, substituted alkene, alkyne, substituted alkyne or with an aryl group (including heterocycles and polynuclear aromatic compounds).
  • Carboxyl groups may be amidated.
  • Carboxyl groups may also be reduced to alcohols, and potentially further converted to alkyl or alkyl halide ethers.
  • Amino groups may be acylated, alkylated or arylated.
  • Benzyl groups may be halogenated, nitrosylated, alkylated, sulfonated or acylated. These modifications are meant to be illustrative and not comprehensive of the types of modifications possible. Modification of the amino acids would likely add to the cost of synthesis and therefore is not preferred.
  • the present invention comprises mixtures containing peptides with antimicrobial activity.
  • Peptide mixtures of the present invention may be selected from an L-hexapeptide library synthesized using the 20 natural amino acids and comprised of equimolar concentrations of all potential combinations of hexapeptides.
  • the hexapeptides are represented by and may be N- and /or C-terminally modified as described above.
  • Each peptide mixture consists of all combinations of hexapeptides wherein D, and D 2 comprise defined amino acids, and U 3 , U 4 , U 5 and U 6 are undefined amino acids.
  • each hexapeptide library consisting of the 160,000 sequences represented by a defined pair of amino acids as D-D 2 , and all possible combinations as U 3 U 4 U 5 U 6 .
  • a single pure peptide demonstrating activity represents 0.000625% by weight of the total weight of the peptide mixture.
  • Preferred amino acids for D, position are arginine (Arg), lysine (Lys), methionine (Met), serine (Ser), threonine (Thr) or tryptophan (Tip).
  • Preferred amino acids for D 2 position are arginine (Arg), histidine (His), cysteine (Cys), threonine (Thr), tyrosine (Tyr) or tryptophan (Tip). Still more preferred are the hexapeptide sequences wherein the first two amino acids (DA) comprise Arg-Tyr, Arg-Cys, Arg-Trp, Ser-Thr, Met-T , Lys-Trp, Thr-Trp, Trp-Arg, Trp-His, Trp-Tyr and Trp-Trp.
  • DA hexapeptide sequences wherein the first two amino acids
  • hexapeptide sequences in which the first two amino acids are (D,D 2 ) ⁇ e Thr-Trp (Thr-Trp-U 3 U 4 U 5 U 6 ).
  • amino acids in positions U 3 , U 4 , U 5 or U 6 may consist of any of the natural amino acids.
  • the peptide of the present invention may be synthesized by solid-phase synthesis as described originally by Merrifield in pages 2149-2154 of J. Amer. Chem. Soc, vol. 85, 1963, and may be modified according to Peptides: synthesis, structures and applications, Gutte B. (ed.), Academic Press, NY, 1995, and Chemical approaches to the synthesis of peptides and proteins, Lloyd- Williams P., Alberico F., Giralt E. (eds.), CRC Press, NY, 1997. Generally, the C-terminal amino acid (with protected N-terminus) is attached to an appropriate solid support via the ⁇ -carboxyl group.
  • the N-terminus is protected by an appropriate protecting group (such as tert-butyloxycarbonyl [Boc] or 9-fluorenylmethoxycarbonyl [Fmoc]).
  • An example of a resin is a copolymer of styrene and l%o divinylbenzene.
  • the N ⁇ -protecting group is removed, and the amino acid that is N-terminal to the attached amino acid is coupled to the attached amino acid using appropriate coupling reagents (such as dicyclohexylcarbodiimide).
  • the peptide is elongated by repeating the deprotection and coupling steps.
  • acyl chain may be attached by a condensation reaction with the N ⁇ -amide of the N-terminal amino acid of a peptide or to the C-terminal amide of the peptide.
  • the acyl chain is added after removal of the Fmoc-group and prior to side chain deprotection.
  • Acetic anhydride may also be used for N-terminal acetylation.
  • an appropriate amide-containing resin is chosen such that when the peptide is cleaved from the resin, the amide group is retained on the peptide.
  • Common solid supports for the synthesis of peptide amides are benzhydrylamide derivatives, such as 4-methylbenzhydrylamine resin. The peptide amide can be cleaved from the resin using hydrogen fluoride.
  • the peptides can be synthesized individually using a parallel synthesis approach, such as the tea bag method of simultaneously synthesizing equimolar amounts of multiple peptides as described in U.S. Patent No. 5,504,190.
  • Other methods of solid-phase synthesis known in the art may also be used to synthesize the peptides of the present invention.
  • the peptides of the present invention were synthesized via solid-phase synthesis by Multiple Peptide Systems (San Diego, CA) according to the above methods. However, the peptides of the present invention may also be synthesized by any known method in the art.
  • Wilson's Salts solution contains (g/1): K 2 HPO 4 , 3.0; KH 2 PO 4 , 1.5; MgSO 4 » 7 H 2 O, 0.1; (NH 4 ) 2 SO 4 , 1.0.
  • the assays were performed in 96-well "U"- bottom microtiter plates (Dynatech Laboratories, Inc., Chantilly, VA) in a total volume of 100 ⁇ l.
  • the assay mixture (final concentration) consisted of 0.25X mTGE, peptide at 625 ppm, and inoculum (2.5 X 10 5 cells/ml).
  • the plates were incubated for 18 h at 30°C, and growth of the organisms was determined by measuring the change in optical density at 540 nm (Spectramax 250, Molecular Devices, Sunnyvale, CA).
  • Antibiofouling compositions for water treatment comprise peptide mixtures of the present invention from about 0.1% to about 50%> by weight of the total composition.
  • Other components in the antibiofouling compositions (used at 0.1% to 50%>) may include:
  • DBNP A glutaraldehyde isothiazolin methylene bis(thiocyanate) triazines n-alkyl dimethylbenzylammonium chloride trisodium phosphate-based antimicrobials tributyltin oxide oxazolidines tetrakis (hydroxymethyl)phosphonium sulfate (THPS) phenols chromated copper arsenate zinc or copper pyrithione carbamates sodium or calcium hypochlorite sodium bromide halohydantoins (Br, Cl) Chlorine rates are based on achieving the appropriate concentration of free halogen.
  • compositions may include biodispersants (about 0.1% to about 15% by weight of the total composition), water, glycols (about 20-30%) or Pluronic (at approximately 7% by weight of the total composition).
  • concentration of antibiofouling composition for continuous or semi-continuous use is about 5 -to about 70 mg/1.
  • Antibiofouling compositions for industrial water treatment comprise peptide mixtures of the present invention from about 0.1% to about 50% by weight of peptide based on the weight of the total composition.
  • the amount of peptide mixture in antibiofouling compositions for aqueous water treatment may be adjusted depending on the particular peptide mixture and aqueous environment. Shock dose ranges are generally about 20 to about 140 mg/1; the concentration for semi-continuous use is about 0.5X of these concentrations.
  • antimicrobial compositions for use as household products include: A. Powder Automatic Dishwashing Composition
  • Peptide mixture 0.00001-50% nonioinic surfactant 0.4-2.5%) sodium metasilicate 0-20%> sodium disilicate 3-20%> sodium triphosphate 20-40% sodium carbonate 0-20%> sodium perborate 2-9%> tetraacetylethylenediamine 1 -4% sodium sulphate 5-33% enzymes, including modified enzymes 0.0001-0.5%)
  • Peptide mixture 0.00001-50% liquid nonionic surfactant 2-10% alkali metal silicate 3-15% alkali metal phosphate 20-40%> liquid carrier selected from higher 25-45%> glycols, polyglycols, polyoxides, glycoethers stabilizer (partial ester of phosphoric 0.5-7%) acid and a C 16 -C 18 alkanol) foam suppressor (silicone) .
  • liquid carrier selected from higher 25-45%> glycols, polyglycols, polyoxides, glycoethers stabilizer (partial ester of phosphoric 0.5-7%) acid and a C 16 -C 18 alkanol) foam suppressor (silicone) .
  • Peptide mixture 0.00001 -50% fatty acid ester sulphonate 0-30% sodium dodecyl sulphate 0-20%o alkyl polyglycoside 0-21% oleic acid 0-10% sodium disilicate monohydrate 18-33% sodium citrate dihydrate 18-33% sodium stearate 0-2.5 %> sodium perborate monohydrate 0-13 %> tetraacetylethylenediamine 0-8% maleic acid/acrylic acid copolymer 4-8%> enzymes, including modified enzymes 0.0001-0.5%>
  • Ci 2 _ 14 alkenyl substituted succinic 0-15% acid sodium hydroxide 0.5-15% ethanol 1-10% monoethanolamine 0-10%
  • compositions for prophylactic or therapeutic treatment include:
  • Peptide mixture 0.000001-20% benzalkonium chloride, parabens or 0-30 % chlorothymol (other antimicrobial agents) phenol or menthol (anesthetic or antipruritics) 10-30 % potassium alum (astringent) 0.4 % or 4 g zinc sulfate (astringent) 0.4 % or 4 g liquefied phenol 0.5-5 % glycerin 10-15 % sodium lauryl sulfate (surface active agent) 20-50 % sodium borate, sodium bicarbonate or citric acid 10-15 %
  • Peptide mixture 0.000001-15% orange oil 0.1-5 % benzaldehyde 0.005-5 % sorbitol solution USP 10-25 % propylene glycol 40-60% alcohol 40-60 % pyrogen-free, sterile water qs to make 100 ml
  • Peptide mixture (solubilized) 0.000001-25% antioxidants (ex: ascorbic acid) 0.5-10 % solvent blends (ex: water, ethanol, glycols) 40-70 %> propellants 5-15 %
  • Peptide mixture (micronized & suspended) 0.000001-25%) dispersing agent (ex: sorbitan trioleate, 40-50 %> oleyl alcohol, oleic acid, lecithin) propellants 5-20 %
  • Peptide mixture 0.000001-20% ammonium chloride 10-25 % dilute ammonia solution 2-20 % oleic acid 5-25 % turpentine oil 15-35 % pyrogen-free, sterile water 50-70 %
  • Peptide mixture 0.000001-20% isopropyl myristate 30-60 %> sorbitan monooleate 1 - 10 % pyrogen-free, sterile water qs to 100 ml
  • Peptide mixture 0.000001-20% soybean oil 5-20% ethanol 10-35 % egg phosphatides 0.5-10 %
  • Myrj 52 polyoxyethylene derivative of fatty acids 0.1-5 % pyrogen-free, sterile water qs to 100 ml
  • Peptide mixture 0.000001-20% propylene glycol esters of capric/caprylic acids 5- 50% polyoxyethylene (50) sorbitan esters 8-20% polyoxyethyleneglycerol triricinoleate 8-20% propylene glycol 20-30%
  • Peptide mixture 0.00001-20% sodium alginate (gelling agent) 2-10 % glycerin 2-10 % methyl hydroxybenzoate 0.1-5 % pyrogen-free, sterile water qs to 100ml
  • Peptide mixture 0.01-15 % anhydrous lanolin 15-40 % mineral oil 5-35 % olive oil 5-35% ethyl alcohol 5-35% pyrogen-free, sterile water 5-20 % glycerin 5-20 %
  • Peptide mixture 0.01-5 % anhydrous lanolin 10-40 % mineral oil 10-40 % olive oil 10-40 %
  • Peptide mixture 0.01-10 % anhydrous lanolin 10-45 % white petrolatum 10-45% olive oil 10-45%
  • Peptide mixture 0.000001 - 10% polyoxyethylene glycol monoester of saturated 5-75 % hydroxylated fatty acid polyethylene glycol 2-50 ml
  • P. Other Parenteral Admixtures Peptide mixture 0.0001-10% soybean oil 5-35 % acetylated monoglycerides 1-25 % egg yolk phosphatides 0.1-10 % glycerol 0.1-10 % pyrogen-free, sterile water qs 100 ml
  • Topical ointments Peptide mixture 0.00001-20% methylparaben 0.1-10 g propylparaben 0.1 - 10 g sodium lauryl sulfate 5-25 %> propylene glycol 5-25 % stearyl alcohol 10-45 % white petrolatum 10-45 % pyrogen-free, sterile water 20-60 %
  • Peptide mixture 0.0001 - 20 % transcutol 5-45 % polyoxyethylene glycolated hydrogenated castor oil 1-15 % transesterified triglyceride (Labrafil) 5-35 %> glycerol monostearate 5-40 % white petrolatum 20-60 %
  • Peptide mixture up to 50% vegetable oil (ex: peanut, cottonseed, soybean) 40-90 % emulsifier (ex: glyceryl monostearate) 1-10 % propellant (ex: propane) 1-10 % W.
  • vegetable oil ex: peanut, cottonseed, soybean
  • emulsifier ex: glyceryl monostearate
  • propellant ex: propane
  • Peptide mixture up to 50% ethanol 46-66 % surfactant (ex: nonionic, anionic or cationic) 0.5-5 % pyrogen-free, sterile water 28-42 % propellant (ex: propane) 3-15 %
  • Peptide mixture 0.0001-15% caprylic acid 2-25 % capric acid 2-25 % lauric acid 5-50 % myristic acid 2-25% palmitic acid 5 -15% stearic acid 5-15 % monoacylglyceride 5-50 % diacylglyceride 5- 40% triacylglyceride 5-60% silicon dioxide 0.05-3 %
  • Examples of doses of pharmaceutical compositions comprising peptides of the present invention include:
  • diseases or infections treatable by pharmaceutical compositions comprising peptide mixtures of the present invention include:
  • Examples of hygiene compositions for personal care use comprising peptide mixtures of the present invention include: A. Facial Cleanser
  • Peptide mixture 0.0001-20% ammonium laureth sulfate 28-32%> disodium EDTA 0.01-0.1% cocamidopropyl betaine 6-9% cocamidopropyl phosphatidyl PG- 1-3% dimonium chloride cocamide DEA 1-3% lactic acid 0-3% glycerin 1-5% propylene glycol, 'imidazolidinyl 0.5-1% urea, methylparaben, propylparaben pyrogen-free, sterile deionized water 50-55% sodium hydroxide 0.5-10%
  • Peptide mixture 0.00001-15% behentrimonium methosulfate, 0.5-4% cetearyl alcohol
  • 1,3-butylene glycol 0.5-15% polyethylene glycol 1500 0.5-15% pyrogen-free, sterile deionized water balance
  • Peptide mixture 0.000001-15% decamethylcyclopentasiloxane 3-50% liquid paraffme 0.5-15% polyoxyalkylene-modified 0.1-5% organopolysiloxane distearyldimethylammonium chloride 0.06-5% perfume 0.03-5% titanium oxide 1-25% zinc oxide 0.5-15% talc 0.2-15% glycerin 0.5-20% magnesium aluminum silicate 0.1-10% pyrogen-free, sterile deionized water balance Lotion
  • Tween 60 0.5-2% ceteareth alcohol 0.5-2% propylene glycol, diazolidinyl urea, 0.5-2% methylparaben, propylparaben glycerin 2-6%
  • Peptide mixture 0.00001-15% stearic acid 0.15-5% cetyl alcohol 0.05-5% polyoxyethylene (10) monooleate 0.2-10%
  • Peptide mixture 0.00001-15% stearic acid 0.2-5% cetyl alcohol .0.05-5% liquid paraffin 1-20% polyoxyethylene (10) oleate 0.1-5% sorbitan trioleate 0.1-5% perfume 0.02-2%
  • 1,3-butylene glycol 0.5-5% dipropylene glycol 0.3-3% carboxyvinyl polymer 0.01-5% trisodium edetate 0.005-3% triethanolamine 0.04-5% silica 0.2-2% talc 0.2-2% titanium oxide 0.3-3% zinc oxide 0.3-3% pyrogen-free, sterile deionized water balance
  • Peptide mixture 0.001-20% pyrogen-free, sterile deionized water 89-92% dimethyl hydroxymethyl pyrazole 0.5-5% panthenol 0.1-0.3% disodium EDTA 0.02-.l% cetearyl alcohol, ceteareth-20 1-2% stearyl alcohol 4-6% cetrimomum bromide 4-6% jojoba oil 0.2-0.5% acetamide MEA 0.5-2% lactamide MEA 0.5-2%
  • Hair Shampoo Peptide mixture 0.001-20% anionic surfactant 5-15% (polyoxyethylenealkyl sulfate) cationic surfactant 0.5-2.5%
  • Antiperspirant/Deodorant Solution Peptide mixture 0.0001-20% aluminum chlorohydrate 10-40% SD alcohol 40 25-35% Transcutol ethoxydiglycol 5-10% Tween 20 0.5-1% cocamidopropyl phosphatidyl PG- 1-2% dimonium chloride pyrogen-free, sterile deionized water 20-25%
  • Mouthwash Peptide mixture 0.001-20% SD alcohol 4-35% selenomethionine 0.2-5% calcium gluconate 0.25-5% L-glutathione 0.10-4% xylitol-sweetener 1-10% coloring agents 0.1-3% flavoring agents 0.1-5% pyrogen-free, sterile deionized water balance
  • Peptide mixture 0.00001-10% glycerol 2-50% magnesium carbonate 0.35-10% sodium fluoride 0.35-10% zinc acetate 0.05-10%
  • N-acetylcysteine 0.01-10% benzalkonium chloride 0.01-10% polyvinyl pyrrolidone 0.75-10% xylitol (sweetner) 0.025-5% coloring agent 0.02-3% peppermint (flavor) 0.02-3% pyrogen-free, sterile deionized water balance
  • Peptide mixture 0.00001-10% glycerin 2-50% poloxamer 10-25% ascorbic acid 0.15-5% sodium lauryl sulfate 0.12-12% peppermint oil 0.1-5% alpha tocopherol 0.075-8% calcium laurate 0.025-5% selenomethionine 0.02-5% sodium fluoride 0.02-5%
  • L-glutathione 0.01-10% coloring agent 0.01-5% xylitol (sweetner) 0.15-20% zinc acetate 0.015-3% pyrogen-free, sterile deionized water balance
  • Body Washes Peptide mixture 0.001-20% dimethylsiloxane-methyl siloxane 0.5-2.5% copolymer potassium cocoyl hydrolyzed 5-40% collagen coconut oil potassium soap (40%) 0.5-15% coconut oil fatty acid 1-15% diethanolamide lauric acid diethanolamide 1-15% p-hydroxybenzoates and 0.05-2.5% phenoxyethanol pyrogen-free, sterile deionized water balance
  • Ointment Peptide mixture 0.00001-20% tocopherol acetate 0.05-5% retinol palmitate 0.1-10% stearyl alcohol 1-30%
  • peptide compositions for medical devices include:
  • suture is dipped in solution above and excess is wiped away with a paper towel for dressing wounds
  • Peptide mixtures of the present invention can be applied by coating or spinning effective amounts of peptide onto or into the desired polymer.
  • the peptides can be prepared in an aqueous solution to use as a coating solution or with a polymer.
  • the coating solutions can contain small water-soluble molecules that do not interfere with the antimicrobial action of the peptide.
  • a peptide and polymer solution or mixture can be made and undergo casting or formation to the desired shaped article, fiber or film. The shaped article, fiber or film can then be put in water or methanol, and air dry or dry under an appropriate atmosphere to prevent oxidative reactions.
  • the resulting solution can be put into a microscale spinning apparatus and fiber is formed while wet with methanol.
  • the antimicrobial activity of the peptides can be tested in tubes containing LB media innoculated with the peptide-containing fiber and E.coli growing at log phase (1 x 10 6 to lx 10 7 cells/ml). Aliquots can be taken from the culture tube at periodic intervals for absorbance readings at 600 nm (uv/vis) in a microcuvette.
  • composition comprising liposomes and acetyl-TWX 3 X 4 X 5 X 6 -NH 2 for inhibition of microbial growth in cell culture at 37°C.
  • Liposome (unilamellar or 2-400 ⁇ g
  • Viable cell counts can be performed after 3 hours to show greater than 90%> reduction in growth of B. cepacia in comparison to control cultures.
  • the antiviral activity of acetyl-TWX 3 X 4 X 5 X 6 -NH 2 may be determined.
  • the peptide is first evaluated for cytotoxicity.
  • Vero cells ATCC CCL81
  • E-MEM Eagles Minimal Essential Medium
  • FBS fetal bovine serum
  • penicillin 100 units/ml
  • penicillin 100 units/ml
  • Amphotericin B 100 units/ml
  • gentamicin total volume 0.2 ml
  • Plates are incubated at 37°C in a humidified atmosphere of 6%> CO 2 .
  • Spent culture medium is removed and each well receives 0.2 ml of the appropriate peptide dilution or cell culture medium (cell control wells).
  • the plates are incubated at 37°C, 6% CO 2 for 4-8 days, after which the cells are examined microscopically and a microtetrazolium assay is performed using 2,3-bis[(phenylamino) carbonyl]-2H-tetrazolium hydroxide (XTT).
  • XTT 2,3-bis[(phenylamino) carbonyl]-2H-tetrazolium hydroxide
  • the peptide mixture is evaluated for antiviral activity using Herpes Simplex Virus Type 1 in a plaque reduction assay.
  • Microtiter plates (24 well) are seeded with Vero cells to confluency. The supernatant medium is removed by aspiration and each well receives 0.5 ml E-MEM with 5% FBS. Virus (0.2 ml) is added to the medium in the test and control wells to achieve 50 plaque-forming units (pfu) per well. After virus attachment the inoculum is removed and replaced with 1 ml medium containing the appropriate dilution of peptide. Plates are incubated at 37°C under 6% CO 2 until plaques are sufficiently well defined to count (2-5 days). The cells are fixed with formalin (10%>) in phosphate buffered saline and stained with crystal violet. Plaques are then counted and the EC 50 (peptide concentration that produces a 50% reduction in plaque fonnation) is calculated.
  • P. falciparum is added as parasite-infected red blood cells (at concentrations ranging from 0.05 to 0.5%o) to flasks containing 50 ml human red blood cells in RPMI 1640 medium plus [ 3 H]-labeled hypoxanthine (10 ⁇ M; 50 ⁇ Ci) for 150 ml final volume.
  • the red blood cells are incubated for 1 week at 37°C under 5% CO 2 .
  • Test peptide e.g., acetyl-TWX 3 X 4 X 5 X 6 -NH 2
  • the cells undergo filtration and hypoxanthine uptake is measured by liquid scintillation counting to detennine P. falciparum viability.
  • sample peptides can be determined using human erythrocytes. Assays are performed in 96-well flat bottom microtiter plates in a total volume of 100 ⁇ l. The assay components (final concentration) are 0.25% human red blood cells (RBCs) and peptide mixture at concentrations of 0 to 500 ⁇ g/ml. Plates incubate for 1 hr at 37°C and then undergo centrifugation at 2800 rpm for 5 min. The supernatant is separated from the pellet and the optical density of the supernatant at 414 nm is measured. The concentration of peptide mixture to lyse 50%> of the RBCs is the hemolytic dose (HD) or HD 50 .
  • HD hemolytic dose

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Animal Behavior & Ethology (AREA)
  • Virology (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Biochemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Genetics & Genomics (AREA)
  • Biophysics (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Pulmonology (AREA)
  • Environmental Sciences (AREA)
  • Water Supply & Treatment (AREA)
  • Agronomy & Crop Science (AREA)
  • Pest Control & Pesticides (AREA)
  • Plant Pathology (AREA)
  • Dentistry (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
  • Environmental & Geological Engineering (AREA)
  • Hydrology & Water Resources (AREA)
  • Biotechnology (AREA)
  • AIDS & HIV (AREA)
  • Cosmetics (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
EP01948413A 2000-06-16 2001-06-15 Peptide, zusammesetzungen und verfahren zur behandlung von burkholderia cepacia Withdrawn EP1292609A2 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US21244000P 2000-06-16 2000-06-16
US212440P 2000-06-16
PCT/US2001/019312 WO2001098364A2 (en) 2000-06-16 2001-06-15 Peptides, compositions and methods for the treatment of burkholderia cepacia

Publications (1)

Publication Number Publication Date
EP1292609A2 true EP1292609A2 (de) 2003-03-19

Family

ID=22791020

Family Applications (1)

Application Number Title Priority Date Filing Date
EP01948413A Withdrawn EP1292609A2 (de) 2000-06-16 2001-06-15 Peptide, zusammesetzungen und verfahren zur behandlung von burkholderia cepacia

Country Status (10)

Country Link
US (1) US20020051819A1 (de)
EP (1) EP1292609A2 (de)
JP (1) JP2004501167A (de)
AU (1) AU2001269866A1 (de)
BR (1) BR0111989A (de)
CA (1) CA2411857A1 (de)
IL (1) IL153359A0 (de)
MX (1) MXPA02012249A (de)
PL (1) PL360507A1 (de)
WO (1) WO2001098364A2 (de)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105350284A (zh) * 2015-12-18 2016-02-24 苏州富美纺织科技有限公司 织物整理液的制备方法
CN107114401A (zh) * 2017-03-29 2017-09-01 岳阳云秋珍珠科技有限公司 一种蓝藻清除剂及其制备方法

Families Citing this family (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FI116030B (fi) * 2002-11-06 2005-09-15 Kemira Oyj Paperi- ja kartonkikoneiden termofiilisten mikrobien biofilminmuodostuksen esto
FI115502B (fi) * 2002-11-06 2005-05-31 Kemira Oyj Bakteerien aiheuttaman kertymänmuodostuksen estäminen paperi- ja kartonkikoneiden pinnoille
GB0413950D0 (en) * 2004-06-22 2004-07-28 Ebiox Ltd Sanitizing method
PL1853620T3 (pl) * 2005-02-09 2012-07-31 Helix Biomedix Inc Heksapeptydy przeciwdrobnoustrojowe
EP1782819A1 (de) * 2005-11-03 2007-05-09 Cognis IP Management GmbH Oligopeptide und deren Verwendung
CN104768523B (zh) 2012-10-29 2017-08-15 宝洁公司 10℃下具有0.30或更大损耗角正切值的个人护理组合物
WO2015021364A1 (en) 2013-08-09 2015-02-12 E. I. Du Pont De Nemours And Company Skin care compositions having cyclic diesters and methods thereof
WO2015084279A1 (en) 2013-12-03 2015-06-11 Istanbul Teknik Universitesi An antibacterial membrane and a production method thereof
US20170000696A1 (en) * 2015-03-24 2017-01-05 The Procter & Gamble Company Methods of applying a high dose of a skin care active to skin with improved sensory benefits to the skin
US20170000711A1 (en) * 2015-03-24 2017-01-05 The Procter & Gamble Company Foam compositions, aerosol products, and methods of using the same to improve sensory benefits to the skin
CN104958283A (zh) * 2015-06-02 2015-10-07 北京盛大康成医疗技术有限公司 弱碱性皮肤粘膜清洗消毒组合物及其制造方法和用途
WO2020250242A1 (en) * 2019-06-10 2020-12-17 Godrej Agrovet Limited Bud break formulation
KR102300142B1 (ko) * 2021-02-03 2021-09-09 엠플러스에프엔씨(주) 밀리터리 패션 스타일 동계용 잠바
KR102300143B1 (ko) * 2021-02-03 2021-09-09 엠플러스에프엔씨(주) 밀리터리룩 스타일 동계용 잠바
KR102300141B1 (ko) * 2021-02-03 2021-09-09 엠플러스에프엔씨(주) 밀리터리 패션 스타일 춘추 잠바
US11806405B1 (en) 2021-07-19 2023-11-07 Zeno Management, Inc. Immunoconjugates and methods

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5328169A (en) * 1976-08-30 1978-03-16 Suntory Ltd Novel peptide and antibacterial agent
CA2090860C (en) * 1990-11-21 2003-09-16 Richard A. Houghten Synthesis of equimolar multiple oligomer mixtures, especially of oligopeptide mixtures
US5786324A (en) * 1994-03-24 1998-07-28 Regents Of The University Of Minnesota Synthetic peptides with bactericidal activity and endotoxin neutralizing activity for gram negative bacteria and methods for their use
US5736533A (en) * 1995-06-07 1998-04-07 Neose Technologies, Inc. Bacterial inhibition with an oligosaccharide compound
US5679364A (en) * 1995-06-07 1997-10-21 Lee County Mosquito Control District Compositions and methods for reducing the amount of contaminants in aquatic and terrestrial environments

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0198364A2 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105350284A (zh) * 2015-12-18 2016-02-24 苏州富美纺织科技有限公司 织物整理液的制备方法
CN107114401A (zh) * 2017-03-29 2017-09-01 岳阳云秋珍珠科技有限公司 一种蓝藻清除剂及其制备方法

Also Published As

Publication number Publication date
WO2001098364A3 (en) 2002-05-16
WO2001098364A2 (en) 2001-12-27
JP2004501167A (ja) 2004-01-15
AU2001269866A1 (en) 2002-01-02
US20020051819A1 (en) 2002-05-02
IL153359A0 (en) 2003-07-06
MXPA02012249A (es) 2004-01-26
BR0111989A (pt) 2003-04-01
CA2411857A1 (en) 2001-12-27
PL360507A1 (en) 2004-09-06

Similar Documents

Publication Publication Date Title
US6858581B2 (en) Chemically-modified peptides, compositions, and methods of production and use
US20030194445A1 (en) Compositions and methods of use of peptides in combination with biocides and/or germicides
US20020051819A1 (en) Peptides, compositions and methods for the treatment of burkholderia cepacia
AU2016203767B2 (en) Compositions and uses of materials with high antimicrobial activity and low toxicity
AU2011289338B2 (en) Bismuth-thiols as antiseptics for agricultural, industrial and other uses
ES2866100T3 (es) Composición y kits para la inhibición de una infección microbiana patogénica y procedimientos para usar los mismos
KR101922409B1 (ko) 화합물들 및 그 용도
US9408393B2 (en) Bismuth-thiols as antiseptics for agricultural, industrial and other uses
US20170247409A1 (en) Abietane-type diterpenoids
BR122019015601B1 (pt) produto, substrato, composição farmacêutica e uso de um produto
WO2010112848A2 (en) Inhibition of biofilm organisms
US20200138033A1 (en) Bismuth-thiols as antiseptics for agricultural, industrial and other uses
WO1997023235A1 (en) Anti-lps factor from horseshoe crabs and methods of use
ES2704703T3 (es) Inhibición de organismos de biopelículas
EP4376957A1 (de) Antimikrobielle pharmazeutische sulfonamidzusammensetzungen zur äusserlichen anwendung
AU2013202832B2 (en) Bismuth-thiols as antiseptics for agricultural, industrial and other uses
EP4376956A1 (de) Halogenaktive aromatische pharmazeutische sulfonamidzusammensetzungen zur inneren anwendung

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20030108

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE TR

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE TR

AX Request for extension of the european patent

Extension state: AL LT LV MK RO SI

17Q First examination report despatched

Effective date: 20031208

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20040621